Tag: autoantibodies

Post COVID and Apheresis – Where are we Standing?

Abstract:

A continual increase in cases of Long/Post COVID constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggest that up to 20% of people with confirmed SARS-CoV-2 suffer from clinically relevant symptoms of Long/Post COVID several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea, and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Post/COVID. Thus, numerous patients are currently treated with apheresis.

However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Post/COVID from centers across Germany.

Source: Steenblock C, Walther R, Tselmin S, Jarzebska N, Voit-Bak K, Toepfner N, Siepmann T, Passauer J, Hugo C, Wintermann G, Julius U, Barbir M, Khan TZ, Puhan MA, Straube R, Hohenstein B, Bornstein SR, Rodionov RN. Post COVID and Apheresis – Where are we Standing? Horm Metab Res. 2022 Nov;54(11):715-720. doi: 10.1055/a-1945-9694. Epub 2022 Sep 16. PMID: 36113501. https://www.thieme-connect.de/products/ejournals/html/10.1055/a-1945-9694 (Full text)

Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants

Abstract:

Chronic fatigue syndrome (CFS), fibromyalgia, silicone breast implants syndrome (SBIs), COVID and post-COVID syndrome (PCS), sick building syndrome (SBS), post-orthostatic tachycardia syndrome (POTS), autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) are frequently accompanied by clinical symptoms characteristic for dysautonomia: severe fatigue, dizziness, fogginess, memory loss, dry mouth and eyes, hearing dysfunction, tachycardia etc.

The recent discovery of an imbalance of autoantibodies against G protein-coupled receptors (GPCR) in some autoimmune diseases, post-COVID syndrome, SBIs allowed researchers to assume the novel mechanism in these conditions – autoimmune autonomic nervous system imbalance.

In this review, all data published on an imbalance of autoantibodies against GPCR, clinical symptoms and pathogenic mechanisms in CFS, Fibromyalgia, SBIs, COVID and PCS, SBS, POTS, and some autoimmune diseases were analyzed. Possible criteria to diagnose the autoimmune autonomic nervous system imbalance were created.

Source: A.M.Malkova, Y.Shoenfeld. Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants. Autoimmunity Reviews, 5 November 2022, 103230. https://www.sciencedirect.com/science/article/abs/pii/S1568997222002002 (Full text)

Persistence of Neutrophil extracellular traps and anti-cardiolipin auto-antibodies in post-acute phase COVID-19 patients

Abstract:

This exploratory prospective study based on 279 individuals showed that plasma levels of neutrophil elastase, myeloperoxidase and circulating DNA of nuclear and mitochondrial origins in non-severe (NS), severe (S) and post-acute phase (PAP) COVID-19 patients were statistically different as compared to the levels in healthy individuals, and revealed the high diagnostic power of these markers in respect to the disease severity. The diagnostic power of NE, MPO, and cir-nDNA as determined by the Area Under Receiver Operating Curves (AUROC) was 0.95, 097 and 0.64; 0.99, 1.0 and 0.82; and 0.94, 1.0, and 0.93, in NS, S and PAP patient subgroups, respectively. In addition, a significant fraction of NS, S as well as of PAP patients exhibited aCL IgM/IgG and anti-B2GP IgM/IgG positivity.

We first demonstrate persistence of these NETs (Neutrophil extracellular traps) markers in PAP patients and consequently of sustained innate immune response imbalance, and a prolonged low-level pro-thrombotic potential activity highlighting the need to monitor these markers in all COVID-19 PAP individuals, to investigate post-acute COVID-19 pathogenesis following intensive care, and to better identify which medical resources will ensure complete patient recovery.

Source: Pisareva E, Badiou S, Mihalovičová L, Mirandola A, Pastor B, Kudriavstev A, Berger M, Roubille C, Fesler P, Klouche K, Cristol JP, Thierry AR. Persistence of Neutrophil extracellular traps and anti-cardiolipin auto-antibodies in post-acute phase COVID-19 patients. J Med Virol. 2022 Oct 13. doi: 10.1002/jmv.28209. Epub ahead of print. PMID: 36226380. https://pubmed.ncbi.nlm.nih.gov/36226380/

Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR).

In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups.

We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients.

Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.

Source: Franziska Sotzny, Igor Salerno Filgueiras, Claudia Kedor, Helma Freitag, Kirsten Wittke, Sandra Bauer, Nuno Sepúlveda, Dennyson Leandro Mathias da Fonseca, Gabriela Crispim Baiocchi, Alexandre H. C. Marques, Myungjin Kim, Tanja Lange, Desirée Rodrigues Plaça, Finn Luebber, Frieder M. Paulus, Roberta De Vito, Igor Jurisica, Kai Schulze-Forster, Friedemann Paul, Judith Bellmann-Strobl, Rebekka Rust, Uta Hoppmann, Yehuda Shoenfeld, Gabriela Riemekasten, Harald Heidecke, Otavio Cabral-Marques, Carmen Scheibenbogen. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. Front. Immunol., 27 September 2022
Sec. Autoimmune and Autoinflammatory Disorders https://doi.org/10.3389/fimmu.2022.981532 (Full text)

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

Abstract:

SARS-CoV-2–infected individuals may suffer a multi–organ system disorder known as “long COVID” or post-acute sequelae of SARS-CoV-2 infection (PASC). There are no standard treatments, the pathophysiology is unknown, and incidence varies by clinical phenotype.

Acute COVID-19 correlates with biomarkers of systemic inflammation, hypercoagulability, and comorbidities that are less prominent in PASC. Macrovessel thrombosis, a hallmark of acute COVID-19, is less frequent in PASC. Female sex at birth is associated with reduced risk for acute COVID-19 progression, but with increased risk of PASC. Persistent microvascular endotheliopathy associated with cryptic SARS-CoV-2 tissue reservoirs has been implicated in PASC pathology.

Autoantibodies, localized inflammation, and reactivation of latent pathogens may also be involved, potentially leading to microvascular thrombosis, as documented in multiple PASC tissues. Diagnostic assays illuminating possible therapeutic targets are discussed.

Source: Ahamed J, Laurence J. Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches. J Clin Invest. 2022 Aug 1;132(15):e161167. doi: 10.1172/JCI161167. PMID: 35912863; PMCID: PMC9337829. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337829/ (Full text)

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

Abstract:

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation.

The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT-angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.

Source: Szewczykowski C, Mardin C, Lucio M, Wallukat G, Hoffmanns J, Schröder T, Raith F, Rogge L, Heltmann F, Moritz M, Beitlich L, Schottenhamml J, Herrmann M, Harrer T, Ganslmayer M, Kruse FE, Kräter M, Guck J, Lämmer R, Zenkel M, Gießl A, Hohberger B. Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation. Int J Mol Sci. 2022 Jun 29;23(13):7209. doi: 10.3390/ijms23137209. PMID: 35806214. https://www.mdpi.com/1422-0067/23/13/7209/htm (Full text)

Autoantibodies against apolipoprotein A-1 after COVID-19 predict symptoms persistence

Abstract:

Background: SARS-CoV-2 infection triggers different auto-antibodies, including anti-apolipoprotein A-1 IgGs (AAA1), which could be of concern as mediators of persistent symptoms. We determined the kinetics of AAA1 response over after COVID-19, and the impact of AAA1 on the inflammatory response and symptoms persistence.

Methods: All serologies were assessed at one, three, six, and twelve months in 193 hospital employees with COVID-19. ROC curve analyses and logistic regression models (LRM) were used to determine the prognostic accuracy of AAA1 and their association with patient-reported COVID-19 symptoms persistence at 12 months. Interferon (IFN)-α and-γ production by AAA1-stimulated human monocyte-derived macrophages (HMDM) was assessed in vitro.

Results: AAA1 seropositivity was 93% at one month and declined to 15% at 12 months after COVID-19. Persistent symptoms at 12 months were observed in 45.1% of participants, with a predominance of neurological (28.5%), followed by general (15%) and respiratory symptoms (9.3%). Over time, strength of correlations between AAA1 and anti-SARS-COV2 serologies decreased, but remained significant. From the 3rd month on, AAA1 levels predicted persistent respiratory symptoms (area under the curves 0.72-0.74; p<0.001), independently of disease severity, age and gender (adjusted odds ratios 4.81-4.94; p=0.02), while anti-SARS-CoV-2 serologies did not. AAA1 increased IFN-α production by HMDMs (p=0.03), without affecting the IFN-γ response.

Conclusion: COVID-19 induces a marked though transient AAA1 response, independently predicting one-year persistence of respiratory symptoms. By increasing IFN-α response, AAA1 may contribute to persistent symptoms. If and how AAA1 levels assessment could be of use for COVID-19 risk stratification remains to be determined

Source: L’Huillier AG, Pagano S, Baggio S, Meyer B, Andrey DO, Nehme M, Guessous I, Eberhardt CS, Huttner A, Posfay-Barbe KM, Yerly S, Siegrist CA, Kaiser L, Vuilleumier N. Autoantibodies against apolipoprotein A-1 after COVID-19 predict symptoms persistence. Eur J Clin Invest. 2022 May 22:e13818. doi: 10.1111/eci.13818. Epub ahead of print. PMID: 35598178.  https://pubmed.ncbi.nlm.nih.gov/35598178/ (Full text available as PDF file)

Case Report: Neutralization of Autoantibodies Targeting G-Protein-Coupled Receptors Improves Capillary Impairment and Fatigue Symptoms After COVID-19 Infection

Abstract:

Clinical features of Coronavirus disease 2019 (COVID-19) are caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Acute infection management is a substantial healthcare issue, and the development of long-Covid syndrome (LCS) is extremely challenging for patients and physicians. It is associated with a variety of characteristics as impaired capillary microcirculation, chronic fatigue syndrome (CFS), proinflammatory cytokines, and functional autoantibodies targeting G-protein-coupled receptors (GPCR-AAbs). Here, we present a case report of successful healing of LCS with BC 007 (Berlin Cures, Berlin, Germany), a DNA aptamer drug with a high affinity to GPCR-AAbs that neutralizes these AAbs.

A patient with a documented history of glaucoma, recovered from mild COVID-19, but still suffered from CFS, loss of taste, and impaired capillary microcirculation in the macula and peripapillary region. He was positively tested for various targeting GPCR-AAbs. Within 48 h after a single BC 007 treatment, GPCR-AAbs were functionally inactivated and remained inactive during the observation period of 4 weeks. This observation was accompanied by constant improvement of the fatigue symptoms of the patient, taste, and retinal capillary microcirculation. Therefore, the removal of GPCR-AAb might ameliorate the characteristics of the LCD, such as capillary impairment, loss of taste, and CFS.

Source: Hohberger B, Harrer T, Mardin C, Kruse F, Hoffmanns J, Rogge L, Heltmann F, Moritz M, Szewczykowski C, Schottenhamml J, Kräter M, Bergua A, Zenkel M, Gießl A, Schlötzer-Schrehardt U, Lämmer R, Herrmann M, Haberland A, Göttel P, Müller J, Wallukat G. Case Report: Neutralization of Autoantibodies Targeting G-Protein-Coupled Receptors Improves Capillary Impairment and Fatigue Symptoms After COVID-19 Infection. Front Med (Lausanne). 2021 Nov 18;8:754667. doi: 10.3389/fmed.2021.754667. PMID: 34869451; PMCID: PMC8637609. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637609/ (Full text)

Autoantibodies to Vasoregulative G-Protein-Coupled Receptors Correlate with Symptom Severity, Autonomic Dysfunction and Disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an acquired complex disease with patients suffering from the cardinal symptoms of fatigue, post-exertional malaise (PEM), cognitive impairment, pain and autonomous dysfunction. ME/CFS is triggered by an infection in the majority of patients. Initial evidence for a potential role of natural regulatory autoantibodies (AAB) to beta-adrenergic (AdR) and muscarinic acetylcholine receptors (M-AChR) in ME/CFS patients comes from a few studies.

Methods: Here, we analyzed the correlations of symptom severity with levels of AAB to vasoregulative AdR, AChR and Endothelin-1 type A and B (ETA/B) and Angiotensin II type 1 (AT1) receptor in a Berlin cohort of ME/CFS patients (n = 116) by ELISA. The severity of disease, symptoms and autonomic dysfunction were assessed by questionnaires.

Results: We found levels of most AABs significantly correlated with key symptoms of fatigue and muscle pain in patients with infection-triggered onset. The severity of cognitive impairment correlated with AT1-R- and ETA-R-AAB and severity of gastrointestinal symptoms with alpha1/2-AdR-AAB. In contrast, the patients with non-infection-triggered ME/CFS showed fewer and other correlations.

Conclusion: Correlations of specific AAB against G-protein-coupled receptors (GPCR) with symptoms provide evidence for a role of these AAB or respective receptor pathways in disease pathomechanism.

Source: Freitag H, Szklarski M, Lorenz S, Sotzny F, Bauer S, Philippe A, Kedor C, Grabowski P, Lange T, Riemekasten G, Heidecke H, Scheibenbogen C. Autoantibodies to Vasoregulative G-Protein-Coupled Receptors Correlate with Symptom Severity, Autonomic Dysfunction and Disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Clin Med. 2021 Aug 19;10(16):3675. doi: 10.3390/jcm10163675. PMID: 34441971. https://pubmed.ncbi.nlm.nih.gov/34441971/

Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome

Abstract:

Context: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe chronic illness which reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.

Objective: To investigate the occurrence of anti-pituitary (APA) and anti-hypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.

Design, setting, patients and other participants: This is a case-control study conducted in University Hospital setting (Stanford, Naples). Thirty women with ME/CSF (Group 1) diagnosed according to Fukuda, Canadian, and IOM criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls.

Main outcome measures: APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands and plasma and urinary osmolality. Both APA and AHA titers were assessed and the prevalence of pituitary hormone deficiencies was also investigated.

Results: Patients in Group 1 showed a high prevalence of AHA (33%) and APA (56%) and a significant lower levels of ACTH/cortisol, and GH peak/IGF1 vs controls (all AHA/APA negative). Patients in Group 1A (13 patients positive at high titers, ≥1:32) showed ACTH/cortisol and GH peak/ IGF1 levels significantly lower and more severe forms of ME/CFS with respect to patients in Group 1B (7 positive at middle/low titers,1:16-1:8) and 1C (10 Ab negative patients).

Conclusions: Both AHA and/or APA at high titers associated with hypothalamic/pituitary dysfunction suggest that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

Source: De Bellis A, Bellastella G, Pernice V, Cirillo P, Longo M, Maio A, Scappaticcio L, Maiorino MI, Bellastella A, Esposito K, Montoya JG. Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome. J Clin Endocrinol Metab. 2021 Jul 13:dgab429. doi: 10.1210/clinem/dgab429. Epub ahead of print. PMID: 34254637. https://pubmed.ncbi.nlm.nih.gov/34254637/